ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago

Interview with Dr Silvia Marsoni (Mario Negri Institute, Milan) and Professor Filippo de Braud (European Institute of Oncology, Milan)

Drug developments presented at ASCO 2010

Thank you for giving us five minutes. Give us some views about ASCO from a Milanese perspective. Now you’ve particularly been looking at the MEK and the MEK stuff and the PI3 kinase stuff, Filippo, what do you think of it?

FDB: Well the session on MEK was really interesting because there were three compound studied in the phase I on more than 270 patients. They saw a lot of activity in patients selected by BRAF mutation but unfortunately among these three compounds, two were behaving the same way and one was a completely different compound for some reason, giving toxicity. So apparently the opinion is that these compounds are going to be very worth combining with others, for example the PI3K in betas in a parallel block, horizontal block, and probably they’re going to be very good even in melanoma BRAF mutated and maybe other diseases with the BRAF mutation. Even better than BRAF inhibitors.

There was some data last year on BRAF mutation melanoma and this year there’s BRAF mutation data on lung?

SM: Colon.

And colon.

FDB: Colon, lung and melanoma again, yes. And among those patients in the MEK session there were a few other diseases with the BRAF mutation that were responding, at least one thyroid cancer I remember. So that is pretty good. They had about three responses among seventeen pancreatic disease with the GSK compound which seems to be very active. There is this quite open question about ocular toxicity, apparently it is reversible and there is the skin rash that is going to be a limit to combining this agent with the other agent on the other pathway.

And the other pathway, the PI3 kinase procedure?

FDB: Well the PI3 kinase session, there were three compounds, two of them studied from the same group and from the same pharma. Actually I must tell you that the other compound was studied better with biopsies done before and after with a pharmacodynamic than on a fresh biopsy studying all the downstream pathways than even the other one. But the feeling is that the drugs are there, we still have a lot to do about them.

Silvia, what do you think?

SM: Yes, actually it was a controversial session because the most interesting compound, which was a PI3K dual  inhibitor, had a lot of clinical pharmacology problems. The pharmacokinetic profile was not linear and the toxicity that you would expect, which is probably also a marker of the class effect, hypoglycemia was only seen with one of the Novartis compounds, with the PI3K alone compound. And the bottom line is it’s too early to say; these are not compounds that are going to work as a single agent, if not in very selected situations – the PI3K mutation tumours, and the combination of these compounds is not going to be simple because of the hypoglycemia problems. There is more work that is needed, but interesting pharmacodynamic overall framework.

What disappointed me is more on the BRAF, the Plexicon  compound that was such an active compound, and still is, in the mutated melanoma. It’s not as active in the same mutation but in the colon – one PR out of 22 patients which is somehow surprising in telling you that mutation alone is not going to ensure that you will have a response. It was interesting there that it’s a drug, it’s a pro-drug, it has a lot of clinical pharmacology glitches and maybe there are other drugs that will be coming around easier to use.

Lex Eggermont said, there is actually another BRAF from, I think, Australia which was looking really very promising and might even overtake the Plexicon.

SM: Yes, I think so.

In melanoma?

SM: Yes. That in melanoma has been confirmed.

PDB: That BRAF, the interesting part is probably there is a pharmacodynamic tool that can be used because in inhibition work if it is below 50% then there is no relation with response. If you have an ERK inhibition above 70-80% you have a very high response rate.

Where do you measure the ERK inhibition?

PDB: You measure it in the biopsy after treatment. And that is something that can be useful because you have somehow a biomarker that they can measure in vivo at least in patients that can be biopsied after the treatment. That also means that probably the inhibition of the pathway is a multiple inhibition, so there is not the one mutation that is responsible.

So there are some quite good little glints of sunshine there. My overall impression is that there’s not a lot of translational science; you described a very good study, by the sound of things, unusually good. Silvia, you were saying that you’re happy to see negative data being presented here and being discussed openly and not being buried under the carpet as has been the accusation in previous times. There were a couple of negative papers: Sunitinib in combination in breasts and so on. Would you like to enlarge on that?

SM: Yes, because ASCO is always a time for hype – the best results tend to be presented and then if the negative one comes later on, they get lost in translation. And that doesn’t help understanding what really happens in a disease. I think that it was very important to present the negative data on Cetuximab, both with the adjuvant trial which really surprised all of us, in colorectal, adjuvant setting, which mimicked what happened with Bevacizumab in an adjuvant setting last year. And also the results of the English trial, the COIN trial which is a complex trial that used FOLFOX6 in combination with Cetuximab which was completely negative, even in the KRAS/BRAF wild type, which was an unexpected result. Again, we will need to pore over the data and understand better what is going to happen there, to try to understand what is happening. But it is creating a reflective mood over CRC which is very good because I think that at the last ASCO it was “KRAS we do this; BRAF we do that; EGFR potentially sensitive we do that.” And it was it a little bit too black and white so now we’re going back to the drawing board, which is obviously a problem but it’s also more realistic. And I think that one of the things that ASCO should do is give a realistic impression of where we are standing with targeted therapy.

PDB: Yes, the talk that Bob Robertson gave at the AACR about the fact that there are many genes involved, drivers and passenger, and most of these genes that are driving the cancer development are not the oncogene but are an oncosuppressor. So that’s as misleading as…

SM: And we don’t have targets for that.

PDB: We should think in a different way, we don’t have a target for that. We noticed today that the P10, which is the only oncogene that we are able to measure, is mutated now in about 15% of the cases that were described in the phase I study. Which is something to think about. Actually more than the expression of HER2 in breast cancer.

SM: I may be skewed, the fact that I have not had time yet to look at the posters where things are really done in detail, but in the oral presentations somehow there is still a tendency to produce a lot of clinical data and not too much pharmacodynamic and pharmacokinetic data. And I think that it should be mandatory, especially in phase 1 and phase 2, to have this data because otherwise you cannot make head nor tail of what is going on.

Now one of the things that I was pleased about was the appearance at the same time, same day, of an article in the New England Journal and the plenary paper here. That solves a lot of issues with explosion of share prices upwards or downwards and the link between the ASCO plenary paper and the share price of some industries has really been regrettable in the past. Now we have, with Ipilimumab for instance, a New England paper and the plenary. And that seems to me to be very reassuring and the way we should go with the really big ones. Because the interesting thing about Ipilimumab is that it’s not focussed on the tumour cells at all and it’s completely independent of any genetic kinase abnormality or anything. It’s suppressing, to use your word, the T-cell suppressor and it’s really looking quite interesting. Are you going to be handling this in other tumour types than melanoma?

PDB: There were the data that were presented in the last year, after the ASCO, about the prostate. I didn’t see anything on prostate this year yet.

SM: I think certainly another place to go and look for it is renal. I do think that this is the melanoma ASCO, for sure. I was also impressed a lot by the toxicity, you are really using an autoimmune disease and who has been using this? SENDO has not done any trial with it, nor are we planning in the near future but people that are entering patients into the melanoma trial, they really think that what you’re doing is you’re inducing Crohn’s Disease in patients. So we’re going to have to figure out a way of handling this. Certainly in a melanoma situation in which you have zero, it’s a good thing. In diseases in which you have alternatives, I would say…

It will have to compete.

SM: Yes.

And the toxicity will be much more important.

SM: And the toxicity will have a much higher weight.

This hypophysitis, this pituitary stuff from this drug is astonishing.

SM: Everything is. I think that immunotherapy is getting a new…

It’s coming through puberty.

SM: Yes, coming through puberty! That’s a good analogy…

It’s getting to adolescence. So it’s going to be a bit toxic for another year or two yet.

SM: Yes, for a couple of years. That’s a very good definition because it’s really up and down, but interesting.

Silvia, a little bit of disappointment on PARP?

SM: Yes, mixed. A lot of joy for the ovarian cancer trial because the data were positive also in the non-BRCA1/2 patients. Disappointment for the negative, triple negative, breast trial where really there was nothing, zero responses. That was surprising because I would have expected to have some activity there so that tells us that we have to go back and look again at what the basic is.

I’ve heard Alan Ashworth talking about BRCAness.

SM: Yes, the famous BRCAness.

From what I’ve been looking at, it seems to me that there is more likelihood that the ovarian cancer patients will be more BRCA-like or BRCAness than the triple negative breast cancer. It’s a massive disappointment for a triple negative breast cancer patient because I know all of us, certainly at IEO, were hoping that this was going to be something.

SM: And there were also a couple of phase I combination with the Olaparib, which when combined with the cytotoxic agents it’s not active, you have to go down the synthetic lethality concept which is one that really should drive the development of these drugs or other drugs.

Hilary Calvert was saying that it’s highly likely that we’re going to be using these PARP inhibitors after drugs like platinum and so on, rather than together because of this dose reduction problem with giving combinations. But it makes a lot of sense and one of the ovarian studies was actually up, wasn’t it?

SM: Absolutely like that.

PDB: And the positive result on BRCA non-mutated is raising the opinion that they can be used in other diseases in combination with platinum. For example there are studies on lung disease and there are going to be studies on pancreatic disease]. I think they are going to be good drugs.

And pancreas, anything on pancreas?

SM: Not that I heard.

A couple of very small gains with one or two combinations. And then the last word, really, on lung and the ALK drug, which again is only 5% of the patients with lung cancer have got this ALK mutation. There are adenocarcinomas that are women, quite often, and non-smokers, so we’re not tackling the major problems with these.

PDB: Yes, but the lung session, for example, wasn’t so positive. Because a big study with the IGFr was negative and toxic in squamous cancers. Also the matter that giving the MEK drug is giving some little advantage in progression free survival but still I think it’s too early to consider this as a drug of the future, even if it’s one of the first positive results with a MEK inhibitor.

And toxicity quite curious- Kerato xanthoma?

PDB: Well kerato xanthoma was already known as a common toxicity of such drugs. We already saw it .

And others?

PDB: Well probably it’s part of the business of inhibition because we have a reactivation of RAS, unmutated RAS so you’re going to develop these kind of diseases.

Silvia and Filippo, thank you very much indeed for taking part in this discussion. I appreciate it very much.